Letter

We thank Oliviero and colleagues for their interest in our recent publication [1] and for reporting their very interesting related experiments [2]. Their results strongly support the concept that extravascular plasma proteins may
act as damage-associated molecular patterns, and specifically as Toll-like receptor
4 agonists. In addition, we note that the NALP-3 inflammasome exhibits dependence
on Toll-like receptor 4 or other mechanisms of priming of IL-1β transcription, thereby
generating pro-IL-1β that can be converted to IL-1β by the activated inflammasome
[3].

Although biochemical measurement of plasma and serum were not performed, we suspect
the enhanced effect of serum compared with plasma could be related to mediators generated
in the clotting process or released by platelets during the clotting process (but
not released in the generation of plasma) and not related to the removal of fibrinogen.
The observation that fibrinogen is itself able to prime the response to calcium crystal-induced
inflammation further supports the role of fibrinogen as a Toll-like receptor 4 agonist
[4,5], as demonstrated by its ability to prime the inflammasome for response to activation
by calcium crystals.

We thank Oliviero and colleagues for sharing their results and look forward to future
studies elucidating the potentially critical role of plasma proteins as extra-vascular
damage-associated molecular patterns.